Dimeric arylisoquinoline alkaloid compounds

ABSTRACT

The present invention provides a method of preparing dimeric arylisoquinoline alkaloids by coupling two isoquinoline building blocks, each of which may be the same or different, together with a symmetrical or nonsymmetrical biaryl building block to form homodimers or heterodimers, including the antiviral michellamines. The present invention also provides new, medically useful homodimeric and heterodimeric arylisoquinoline compounds and derivatives thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application is a continuation of U.S. Ser. No. 08/305,211,filed on Sep. 13, 1994, now abandoned, which, in turn is acontinuation-in-part of both U.S. patent application Ser. No.08/279,291, filed Jul. 22, 1994, now allowed, and U.S. patentapplication Ser. No. 08/279,339, filed Jul. 22, 1994, now allowed.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to methods of preparing known and newdimeric arylisoquinoline alkaloids. In complement to other methods, thepresent invention provides more efficient or otherwise advantageousaccess to a broader range of medically useful compounds. The presentinvention also relates to new dimeric arylisoquinoline compounds andderivatives thereof.

BACKGROUND OF THE INVENTION

Novel compounds exhibiting impressive antiviral and/or antiparasiticproperties have recently been described (Manfredi et al., J. Med. Chem.,34, 3402-3405, (1991); Bringmann et al., Angew. Chem. Int. Ed. Eng., 32,1190-1191, (1993); Boyd et al., J. Med. Chem., 37, 1740-7815, (1994);Boyd et al., U.S. Pat. No. 5,455,251; Bringmann et al , Tetrahedron, 50,7807-7815, (1994); Hallock, et al., J. Org. Chem., 59, 6349-55 in press,(1994); Bringmann, et al., Heterocycles, 39, 503-512 (1994) in press,1994b; Bringmann et al., Tetrahedron, 20, 9643-9648, (1994b); Françoiset al., Phytochemistry, 35, 1461-1464, (1994); François et al., PCTApplication PCT/US95/01717; Boyd et al., U.S. Pat. No. 5,409,938;Bringmann et al., U.S. patent application Ser. No. 08/279,291; andBringmann et al., U.S. patent application Ser. No. 08/279,339). Thesecompounds are members of a general class known as naphthylisoquinolinealkaloids (Bringmann, The Alkaloids, Vol. 29 (Brossi, ed.), AcademicPress, New York, 1986, pp. 141-184), and can further be characterizedbased on their structure as either monomeric alkaloids (or "monomers")or dimeric alkaloids (or "dimers").

Monomeric alkaloids include korupensamines or related monomericnaphthylisoquinoline alkaloids and derivatives thereof, which typicallypossess a C-8' to C-5 naphthalene/isoquinoline linkage, andnon-korupensamines or other monomeric naphthylisoquinoline alkaloids andderivatives thereof, which typically lack a C-8' to C-5naphthalene/isoquinoline linkage.

Dimeric alkaloids include michellamines, which based on their molecularstructure are comprised of two monomeric alkaloids coupled together(e.g., two monomeric or molecular "halves"). Furthermore, a givenmichellamine may be either "homodimeric" (comprised of two monomerichalves which are the same) or "heterodimeric" (comprised of twomonomeric halves which are different).

Dimeric naphthylisoquinoline alkaloids, as exemplified by themichellamines, have highly desirable and eminently useful medicinalproperties that for the most part are distinct from the properties ofthe monomeric naphthylisoquinoline alkaloids which comprise theirmolecular halves. For example, the michellamines, such as michellamine B(Boyd et al., U.S. Pat. No. 5,455,251; Boyd et al., 1994, supra) arehighly effective inhibitors of the replication and resultant destructiveeffects of the human immunodeficiency virus (HIV) in human immune cells.The range of anti-HIV activity observed for these dimeric alkaloids isexceptionally broad, encompassing both the major viral types, HIV-1 andHIV-2, as well as diverse HIV strains, and can be observed in differenthost cells (Boyd et al., 1994, supra).

Moreover, the dimeric alkaloids would appear to comprise a novelantiviral drug class in that the mechanism of action of themichellamines is distinct from any mechanism previously described.Specifically, the mechanism involves at least two components: (1) aninhibition of the viral reverse transcriptase, and (2) an inhibition ofthe cell-cell fusion process (McMahon et al., Antimicrob. AgentsChemother., 35, 484, 488 (1995)). This suggests that the dimericalkaloids may prove effective not only in the prevention of nascentviral infection, but also in the prevention of the replication andspread of the virus in vivo and in the prevention of syncytia formationwhich has been observed in vitro and which may mediate the depletion ofT4 immune cells which occurs in vivo.

In addition to the medicinally desirable properties of the dimericalkaloids, they are also quite attractive from a pharmacological andtoxicological standpoint. In vivo doses of michellamine B that arenon-toxic result in a level of the drug in the blood which is well inexcess of its effective antiviral concentration (Supko et al., Anal.Biochem., 216, 52-60, (1994); Supko et al., Antimicrob. AgentsChemother., 9-14 (1995)).

In contrast, the monomeric naphthylisoquinoline alkaloids appear to bedevoid of anti-HIV activity. However, the monomeric alkaloids insteadhave potent antiparasitic properties as exhibited by their activityagainst strains of malaria-causing organisms. In this respect, it isinteresting to speculate that a trace of this antiparasitic activity maybe imparted to the alkaloid dimer by its constituent monomeric halves,as a few of the dimeric naphthylisoquinoline alkaloids (e.g., themichellamines) also appear weakly antiparasitic (Boyd et al., U.S. Pat.No. 5,409,938; François et al., PCT Application PCT/US95/01717; Françoiset al., 1994, supra).

Unfortunately, attempts by researchers to maximally exploit thepotential of the dimeric alkaloids through development of antiviral andantiparasitic therapy and unprecedented uses for the alkaloids have beenhindered by the lack of significant access to the dimeric alkaloids. Todate, the only known natural source of the dimeric alkaloids is the raretropical vine Ancistrocladus korupensis of Central Africa (Thomas andGereau, Novon 3, 494-498 (1993); Boyd et al., 1994, supra; Hallock etal., 1994, supra). The U.S. National Cancer Institute has activelysolicited the research community to engage in efforts to discovermethods of synthesis of these compounds, as well as synthesis ofimproved compounds (Anonymous, J. Nat. Prod., 55, 1018-1019, (1992)).

To address the critical need for synthetic access to michellamines andother medically useful known and new dimeric naphthylisoquinolinealkaloids, a recent, previous invention provided a method of preparationof such compounds by the coupling together of two selected synthetic ornaturally occurring monomeric naphthylisoquinoline alkaloids (Bringmannet al., U.S. patent application Ser. No. 08/279,339). More specifically,the previous invention provided a method of preparing anaphthylisoquinoline alkaloid dimer comprising the steps of (a)selecting first and second naphthylisoquinoline alkaloid monomers, whichare either the same or different, (b) optionally introducing protectivegroup(s) at desired site(s) in the monomers, (c) introducing activationgroup(s) at the desired coupling site(s) of the monomers if needed forcoupling of the monomers, (d) coupling the first and second monomers toform a dimeric naphthylisoquinoline alkaloid, and (e) optionallyremoving the protective group(s) from the dimeric naphthylisoquinolinealkaloid.

Thus, in the method of the previous invention, the pre-selected orpre-constructed naphthylisoquinoline monomers, each of which alreadycontains a naphthalene-to-isoquinoline linkage, are coupled together toform the central biaryl axis (naphthalene-to-naphthalene) comprising thedimer. For any particular dimeric compound needed or sought bysynthesis, however, an alternate method of preparation providing moreefficient or otherwise advantageous access to the naphthylisoquinolinealkaloid dimer would be highly desirable and useful. It would beparticularly desirable, for example, to have an alternate method whichdoes not require the use of pre-selected or pre-constructed monomericnaphthylisoquinoline monomers, which may not be immediately orefficiently available. An alternate method providing access not only toknown dimeric naphthylisoquinoline alkaloids but also to unprecedentednew dimeric arylisoquinolines would be even more desirable.

Accordingly, it is an object of the present invention to provide a newmethod for synthesizing dimeric arylisoquinoline alkaloids. The distinctnovelty of the synthetic strategy is the intermolecular biaryl couplingof intact isoquinoline building blocks to the biaryl centerpiececomprising the desired dimeric product. This synthetic strategy bearssome similarities to that disclosed in the method of yet anotherprevious invention which incorporates the intermolecular biaryl couplingof an isoquinoline building block with a naphthalene building block toform a monomeric naphthylisoquinoline alkaloid (Bringmann et al., U.S.patent application Ser. No. 08/279,291). This and other objects andadvantages of the present invention, as well as additional inventivefeatures, will be apparent from the description of the inventionprovided herein.

BRIEF SUMMARY OF THE INVENTION

The present invention provides a method of preparing a dimericnaphthylisoquinoline alkaloid comprising (a) obtaining first and secondisoquinoline building blocks, which are either the same or different,each having protective group(s) at desired site(s), each containing anactivation group at a desired coupling site, and each being atetrahydroisoquinoline, dihydroisoquinoline, or fully aromaticisoquinoline building block, (b) obtaining a biaryl building blockhaving protective group(s) at desired site(s), a first activation groupat a first desired coupling site, and a second activation group at asecond desired coupling site, (c) coupling the first isoquinolinebuilding block at the desired first coupling site, (d) coupling thesecond isoquinoline building block at the second coupling site of thebiaryl building block, and (e) optionally deprotecting desired site(s)on the biaryl building block.

The present invention also provides new dimeric arylisoquinolinealkaloids, as well as derivatives thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the structures of michellamine A (1a) andmichellamine B (1b).

FIG. 2 illustrates the preparation of the suitably protected andactivated biaryl building block (6) for synthesis of michellamines A andB. Reaction conditions: a) 0° C., THF, 2 h; stand on silica gel at rt 24h, 70%; b) Mel, Ag₂ O, reflux 1 h, 97%; c) DMF, copper bronze,Pd(PPh₃)₄, 1.5 h, 130° C. (convert crude directly to 5); d) Zn, Ac₂ O,NaOAc, DMAP, CH₂ Cl₂, rt, 10 h, 43% overall from 4; d) CH₂ Cl₂ /MeOH,DBU, rt 15 min, 70%; f) CH₂ Cl₂, 2,6-lutidine, Tf₂ O, rt, 30 min, 79%.

FIG. 3 illustrates the selection and further preparation of suitablyprotected and activated isoquinoline building block(s), their couplingto the biaryl building block (6), and subsequent deprotection andseparation of the product michellamines (1a and 1b of FIG. 1). Reactionconditions: a) n-BuLi, THF, B(OMe)₃, -78° C. to rt, aqueous workup, 89%;b) Pd(PPh₃)₄, Ba(OH)₂, DME/H₂ O, 80° C., 8 h, 74%; c) H₂, Pd/C (10%), 1atm, EtOH, 3d; d) methanolic HCl, reflux 10 h, 85% from 9; e)atropoisomer separation as reported previously (Boyd et al., J. Med.Chem., 37, 1740-1745, 1994).

FIG. 4 illustrates the preparation of a biaryl building block byoxidative phenolic coupling. Typical reaction conditions are: a) BCl₃,CH₂ Cl₂ ; b) FeCl₃ H₃ CCN; c) Zn, HOAc; d) AcCl, NEt₃, DMAP, CH₂ Cl₂.

FIGS. 5A-B illustrate other approaches to the preparation of differentbiaryl building blocks. For FIG. 5A, typical reaction conditions are: a)BCl₃, CH₂ Cl₂ ; b) SEM-Cl, PTC, 2N NaOH, CH₂ Cl₂ ; c) t-BuLi, Et₂ O,-78° C.; d) CuCN; e) O₂, -78° C.; f) t-BuLi, Et₂ O, -78° C.; g) C₂ Br₂Cl₄. For FIG. 5B typical reaction conditions are: a) Bcl₃, CH₂ Cl₂ ; b)Cu (Ac)₂, NH₃, 2,6-xylenol; c) AcCl, NEt₃, DMAP, CH₂ Cl₂.

FIGS. 6A-B illustrate various routes of preparation of biphenyl andphenylnaphthalene building blocks. For FIG. 6A, typical reactionconditions are: a) BBr₃, CH₂ Cl₂, 0° C.; b) i-C₃ H₇ Br, K₂ CO₃, acetone,reflux; c) Br₂, HOAc, NaOAc, rt. For FIG. 6B, typical reactionconditions are: a) Br₂, tert-BuNH₂, toluene; b) n-BuLi, -78° C., THF; c)B(OMe)₃, THF, aqueous workup; d) Pd(PPh₃)₄, Ba(OH)₂, DME/H₂ O; c) Br₂,CH₂ Cl₂.

FIGS. 7A-B illustrate various routes of preparation of differentisoquinoline building blocks. FIG. 7A shows examples for preparation ofelectrophilic isoquinoline building blocks; typical reaction conditionsare: a) Br₂, tert-BuNH₂, toluene; b) BnBr, K₂ CO₃, acetone; c) BnBr, K₂CO₃, acetone; d) Br₂, CH₂ Cl₂ ; e) Tf₂ O, TlOEt, CH₂ Cl₂. FIG. 7B showsexamples for preparation of nucleophilic isoquinoline building blocks;typical reaction conditions are: a) BnBr, K₂ CO₃, acetone; b) n-BuLi,-78° C., THF; c) B(OMe)₃, THF, aqueous workup; d) BnBr, K₂ CO₃, acetone;e) Br₂, DMF; f) n-BuLi, -78° C., THF; g) B(OMe)₃, aqueous workup.

FIG. 8 illustrates preparation of a nonsymmetrical dimericarylisoquinoline alkaloid by sequential coupling of different first andsecond isoquinoline building blocks to a biaryl building block. Typicalreaction conditions are: a) BCl₃, CH₂ Cl₂ ; b) Cu (OAc)₂, NH₃,2,6-xylenol; c) BnBr, K₂ CO₃, acetone; d) n-BuLi (1 eq), NCS, Et₂ O; e)Pd(PPh₃)₄, Ba(OH)₂, DME/H₂ O; f) n-BuLi, C₂ Br₂ Cl₄, THF; g) Pd(PPh₃)₄,Ba(OH)₂, DME/H₂ O; h) H₂, Pd/C(10%), EtOH.

FIGS. 9A-G illustrate other specific examples of dimericarylisoquinoline alkaloids which can be prepared according to the methodof the present invention. FIGS. 9A-9D show symmetrical homodimerswherein the central biaryl core is a binaphthalene or biphenyl, and theisoquinoline parts are identical; FIGS. 9E-9G show nonsymmetricalheterodimers, wherein the isoquinoline parts are not identical and/orwherein the central biaryl core is nonsymmetrical (e.g., such as aphenylnaphthalene).

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides methods of preparing both known and newdimeric arylisoquinoline alkaloids and derivatives thereof. The presentinvention also provides new dimeric arylisoquinoline compounds andderivatives thereof.

Definitions

For clarification of the chemical structures described herein, thefollowing definitions apply.

By arylisoquinoline homodimer is meant a dimeric alkaloid containing twomonomeric arylisoquinoline halves, wherein each half is the same.

By arylisoquinoline heterodimer is meant a dimeric alkaloid containingtwo monomeric arylisoquinoline halves, wherein each half is different.

By C₁ -C₆ alkyl is meant straight or branched-chain C₁ -C₆ alkyl groups.Examples include, but are not limited to, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tertiary-butyl, n-pentyl,isopentyl, and n-hexyl.

By aryl is meant an organic radical derived from an aromatichydrocarbon. Examples of aryl groups include phenyl, o-, m-, andp-hydroxyphenyl, and naphthyl.

By aliphatic is meant an organic radical derived from an openhydrocarbon chain. Examples of aliphatic radicals include alkanes,alkenes, and alkynes. Specific examples of aliphatic radicals which canbe used in the present invention include, but are not limited to, C₁ -C₆alkyl radicals, straight or branched.

Medical and Other Uses

The new dimeric arylisoquinoline alkaloids and derivatives thereof areexpected to have at least those medicinal properties possessed by thepreviously known dimeric naphthylisoquinoline alkaloids (see, e.g., Boydet al., U.S. Pat. No. 5,455,251; Boyd et al., 1994, supra). However,depending upon the particular disease and host to be treated, a compoundof the present invention will be distinctly advantageous in a givensituation.

Medically useful properties of the compounds of the present inventioncan be readily confirmed by one knowledgeable and skilled in the art byuse of any of a variety of methods which have been published orotherwise disclosed elsewhere. For example, antiviral properties,particularly anti-HIV properties, can be confirmed as described in Boydet al., J. Med. Chem., 1994, supra, and Boyd et al., U.S. Pat. No.5,455,251. Also, for example, in vitro and in vivo antimalarial activitymay be confirmed as described in François et al., Phytochemistry, 35,1461-1464 (1994), Gulakowski et al., J. Virol. Methods, 33, 87-100(1991), François et al., PCT Application PCT/US95/01717, and Boyd etal., U.S. Pat. No. 5,409,938.

The compounds of the present invention are also useful in a variety ofin vitro applications. Such in vitro applications include biochemicalassays, as well as chemical syntheses and viral research.

Synthesis of Dimeric Arylisoquinoline Alkaloids

The present inventive method of preparing a dimeric arylisoquinolinealkaloid comprises the steps of:

(a) obtaining first and second isoquinoline building blocks, which areeither the same or different, each having protective group(s) at desiredsite(s), each containing an activation group at a desired coupling site,and each being a tetrahydroisoquinoline, dihydroisoquinoline, or fullyaromatic isoquinoline building block,

(b) obtaining a biaryl building block having protective group(s) atdesired site(s), a first activation group at a first desired couplingsite, and a second activation group at a second desired coupling site,

(c) coupling the first isoquinoline building block at the desired firstcoupling site,

(d) coupling the second isoquinoline building block at the secondcoupling site of the biaryl building block, and

(e) optionally deprotecting desired site(s) on the biaryl buildingblock.

While the foregoing steps can be utilized to prepare a dimericarylisoquinoline alkaloid in accordance with the present invention, theorder of several of the aforesaid steps of the present inventive methodare not critical. For example, the first and second isoquinolinebuilding blocks can be simultaneously coupled to the biaryl buildingblock. Alternatively, the second activation group can be introduced atthe second desired coupling site in the biaryl building block after thefirst isoquinoline building block is coupled to the biaryl buildingblock, with the second isoquinoline building block being coupled to thebiaryl building block after the first isoquinoline building block iscoupled to the biaryl building block. In that instance, the desiredsite(s) on the biaryl building block can be deprotected prior tointroducing the second activation group at the second desired couplingsite in the biaryl building block.

Preferably, the present inventive method further comprises:

(f) removing the protective groups from the dimeric arylisoquinolinealkaloid, and

(g) purifying the dimeric arylisoquinoline alkaloid.

When the first and second isoquinoline building blocks are the same,then their coupling to a symmetrical biaryl building block results in ahomodimeric arylisoquinoline alkaloid. Alternatively, when the first andsecond isoquinoline building blocks are different, then their couplingto a symmetrical biaryl building block results in a heterodimericarylisoquinoline alkaloid. The coupling of same or different first andsecond isoquinoline building blocks to a nonsymmetrical biaryl buildingblock also results in a heterodimeric arylisoquinoline alkaloid.

Any suitable building blocks can be utilized. The isoquinoline buildingblocks can have the configurations at any chiral centers as desired inthe dimeric arylisoquinoline alkaloid. For example, when theisoquinoline building block is a tetrahydroisoquinoline building block,the tetrahydroisoquinoline building block might preferably have methylgroups at C-1 and C-3, and these chiral centers might preferably havethe R-configuration at C-1 and the R-configuration at C-3, theS-configuration at C-1 and the R-configuration at C-3, theR-configuration at C-1 and the S-configuration at C-3, or theS-configuration at C-1 and the S-configuration at C-3. Similarly, whenthe isoquinoline building block is a dihydroisoquinoline building block,the dihydroisoquinoline building block might preferably have a methylgroup at C-3 and might preferably have either the S-configuration or theR-configuration at C-3. The biaryl building block can be any suitablesymmetrical biaryl building block, such as, for example, a binaphthaleneor a biphenyl, or it might be a nonsymmetrical biaryl building block,such as phenylnaphthalene.

Any suitable activation and protective groups can be utilized withrespect to any of the building blocks. One or both of the activationgroups, used either on the biaryl or on the first and secondisoquinoline building blocks, will generally be a nucleophilicactivation group, while the other of the activation groups, on the otherbuilding block(s), will generally be an electrophilic activation group.The first and second activation groups for the biaryl building block arepreferably electrophilic activation groups. The activation groups forthe first and second isoquinoline building blocks are preferablynucleophilic activation groups. The nucleophilic activation groups arepreferably selected from the group consisting of boronic acid andtrialkylstannyl groups. The electrophilic activation groups arepreferably selected from the group consisting of halogens, particularlybromine, and O-triflate leaving groups. Introduction of the activationgroup may be accomplished by any suitable means, for example, bymetallation followed by conversion to an activation group, such astrialkylstannyl or a boronic acid derivative. Protective groups arepreferably selected from the group consisting of benzyl, acyl, formyl,and isopropyl groups.

In the aforementioned method, when the first and second isoquinolinebuilding blocks are the same, the couplings of the first and secondisoquinoline building blocks to the biaryl building block are preferablydone simultaneously (e.g., in one step using two equivalents of theisoquinoline building block and one equivalent of the biaryl buildingblock). If the first and second isoquinoline building blocks aredifferent, then, optionally, the suitably activated and protected firstisoquinoline building block may be coupled to the suitably activated andprotected biaryl building block; then, optionally, any protectivegroup(s) is (are) removed as necessary, and the second activation groupis introduced at the desired coupling site, followed by coupling of thesuitably activated and protected second isoquinoline building block.

The aforementioned process steps can be carried out by any suitablemeans. Thus, for example, the coupling can be effected by several means,such as by transition metal catalysis, especially by using Pd. Also, thedimeric arylisoquinoline alkaloid can be purified by a variety of means,preferably by HPLC. The purification of the dimeric arylisoquinolinealkaloid is more preferably carried out by HPLC on an amino-bonded orother phase column so as to obtain a pure atropodiastereomer. Moreover,while the purification process is preferably carried out after removalof the protective groups, the purification process can be carried outeither before or after the removal of the protective groups.

The protective group(s) can be removed from the dimeric arylisoquinolinealkaloid by any suitable means, preferably by using methanolic HCl andby hydrogenolysis. Also, following synthesis, the dimericarylisoquinoline alkaloid can be purified by any suitable means,preferably by HPLC, and especially on an amino-bonded or other phasecolumn.

Accordingly, the method of the present invention can be used to obtainany of the dimeric arylisoquinoline compounds of previous inventions, inparticular those disclosed in (Boyd et al.) and U.S. Pat. No. 5,455,251Ser. No. 08/279,339 (Bringmann et al.). Michellamines A and B (1a and 1bin FIG. 1, respectively) are examples of such compounds. Themichellamines are a type of dimeric arylisoquinoline alkaloid in whichthe biaryl core is a binaphthalene. The synthesis of michellamines A andB provides a more specific illustration of the method of the presentinvention.

Synthesis of Michellamines

Michellamines A and B have identical 1R,3R-configuredtetrahydroisoquinoline parts, but differ with respect to theconfigurations at the biaryl axes (Boyd et al., 1994, supra; Bringmannet al, 1993; Bringmann et al., 1994a, supra; Bringmann et al., 1994b,supra). Curiously, the third possible atropoisomer, michellamine C, doesnot appear to co-occur naturally, although equilibration of 1a and 1bproduces a mixture of all three michellamines A, B, and C (Boyd et al.,1994, supra). With the central axis not being configurationally stable,michellamines A, B and C constitute the complete series ofatropodiastereomers with respect to the stereogenic axes between theisoquinoline and the naphthalene parts. A recently disclosed (Bringmannet al., 1994b, supra) first total synthesis of michellamine A (1a) wasaccomplished by the method of a previous invention (Bringmann et al.,U.S. patent application Ser. No. 08/279,339) by oxidative coupling ofthe appropriately protected corresponding monomeric naphthylisoquinolinealkaloid, named korupensamine A (Hallock et al., supra), which itselfhad also been synthesized (Bringmann et al., 1994b, supra). In themethod of the present invention, the non-biomimetic total synthesis ofboth michellamines A and B can be accomplished by a complementarystepwise construction of the biaryl axes, forming first the(configurationally unstable) central axis and then, simultaneously, thetwo (stereogenic) outer ones. A more specific illustration of the methodfollows below.

Given the constitutionally symmetric structure of the michellamines, thepreferable synthesis of these particular compounds comprises the doubleintermolecular coupling of a central binaphthalene building block withtwo equivalents of an appropriately protected, enantiomerically puretetrahydroisoquinoline building block. The synthesis is outlined inFIGS. 2 and 3. For the required binaphthalene unit 6, acetate groups areselected for the protection of the O-functionalities and triflate groupsfor the activation of the coupling positions.

The preparation of the binaphthalene building block 6 starts with theknown (Casey et al., J. Org. Chem., 46, 2089-2092, (1981); Savard andBrassard, Tetrahedron, 40, 3455-3464, (1984) diene 3, available in onestep from methyl 3,3-dimethyl-acrylate by successive treatment withlithium diisopropylamide and trimethylsilyl chloride. The2,6-dibromobenzoquinone (2) is prepared by the oxidation of2,4,6-tribromophenol with fuming nitric acid (Hodgson et al., J. Chem.Soc., 1085-1087, (1930)); a CH₂ Cl₂ solution of the crude is passedthrough a column of silica gel. The Diels-Alder reaction of 3 with 2proceeds regiospecifically, as expected from Savard and Brassard (1984,supra) to give, after aromatization of the adduct, ahydroxynaphthoquinone, which is converted to its methyl ether 4. This isthen dimerized using copper bronze (Shimizu et al., Tetrahedron Lett.,34., 3421-3424, (1993)) and reductively acetylated (Farina et al.,Tetrahedron, 38, 1531-1537, (1982)) to afford tetraacetate 5. Analternate synthesis of the intermediate diquinone (not shown;intermediate between 4 and 5) may be prepared according to Laatsch(Liebigs Ann. Chem., 1321-1347, (1980)). The two less-hindered acetategroups in 5 are selectively cleaved by treatment withdiazabicycloundecene (DBU) in methanol (Baptistella et al., Synthesis,436-439, (1989)) to generate a diol, which is converted to ditriflateusing Tf₂ O in CH₂ Cl₂ and 2,6-lutidine as a base.

The next steps are the selection and coupling of the isoquinolinebuilding blocks. With the central biaryl axis thus established in thebiaryl building block, and the required coupling positions thereinactivated by O-triflate substituents, the construction of the outerbiaryl axes is then approached. The steps are illustrated in FIG. 3. Assuitable building block(s) for the particular heterocyclictetrahydroisoquinoline system comprising the michellamines, thecorrectly configured, enantiomerically pure boronic acid e, havingbenzyl group protection for the O- and the N-functionalities, isselected. This building block is prepared from the known (Bringmann etal., 1994b, supra) corresponding bromo compound 7, by lithiation andtreatment with freshly distilled B(OMe)₃, followed by aqueous workup.Reaction of 6 and 8 in the presence of Pd(PPh₃)₄ and Ba(OH)₂, in DME/H₂O as a solvent (Watanabe et al., Synlett., 207-210, (1992); Suzuki, PureAppl. Chem., 213-222, (1994)), provides the quateraryl 9, with all thering systems correctly linked to each other, as a mixture ofatropodiastereomers. Removal of all O- and N-protecting groups finallyyields a mixture of the atropodiastereomeric michellamines 1a and 1b,which can then be resolved, if desired, as described previously(Manfredi et al., 1991, supra; Boyd et al., 1994, supra). The synthetic1a and 1b can readily be shown to be identical, by direct comparison, toauthentic, naturally derived materials. More specific details of asynthesis of michellamines A and B, illustrating further the presentinvention, are provided in Example 1.

Synthesis of Derivatives and Other Modified Dimeric ArylisoquinolineAlkaloids

One skilled in the art will readily appreciate that certain chemicalmodifications can be incorporated as desired into the method of thepresent invention, and/or can be used to modify the end product thereof,to obtain a useful synthetic dimeric arylisoquinoline alkaloidderivative. Such modified properties can include greater therapeuticpotency against a particular disease or disease-causing organism, abroader spectrum of therapeutic activity against diverse diseases ordisease-causing organisms, enhanced oral bioavailability, less toxicityin a particular host mammal, more advantageous pharmacokinetics and/ortissue distribution in a given host mammal, and the like. For example,by applying one or more well known chemical reactions (such asexemplified in previous disclosures (Boyd et al., U.S. Pat. No.5,455,251; Bringmann et al., U.S. patent application Ser. No.08/279,339) to a given dimeric arylisoquinoline alkaloid, preparedaccording to the aforementioned method, a useful new derivative may beobtained wherein one or more phenolic hydroxyl group(s) may instead bereplaced by an ester, sulfonate ester, or ether group, one or moremethyl ether group(s) may instead be replaced by a phenolic hydroxylgroup, one or more phenolic hydroxyl group(s) may instead be replaced byan aromatic hydrogen substituent, a secondary amine site may instead bereplaced by an amide, sulfonamide, tertiary amine, or alkyl quaternaryammonium salt or corresponding Hoffmann elimination product thereof, atertiary amine site may instead be replaced by a secondary amine, andone or more aromatic hydrogen substituent(s) may instead be replaced bya halogen, nitro, amino, hydroxyl, thiol, acyl, C₁ -C₆ alkyl, or cyanosubstituent, and CH₃ may be replaced by H. Alternatively, if a"modified" dimeric alkaloid is desired, such modifications can becontained or incorporated within the isoquinoline and/or biaryl buildingblocks used to synthesize the dimer. For example, a useful modifiedcompound can be obtained by the method of the present invention byselecting and constructing, and incorporating in the coupling step(s),an appropriately protected and activated tetrahydroisoquinoline,dihydroisoquinoline, or fully aromatic isoquinoline building block,having any desired different configurations at any present chiralcenter(s), and having any desired different substituent(s) at anyavailable ring position(s). Further illustrations of obtaining differentbiaryl and isoquinoline building blocks are given in Examples 2 and 3,respectively.

Synthesis of Novel Dimeric Arylisoquinoline Alkaloids and Derivatives

Given the present disclosure, it will be apparent to one skilled in theart that unprecedented new useful dimeric arylisoquinoline compounds canbe prepared by the method of the present invention. For example,variations in either or both of the isoquinoline building blocks and/orin the biaryl building block may be incorporated in the method to giveunprecedented compounds. In particular, variations in the biarylbuilding block can be incorporated into the method to make new dimers,which lack the central binaphthalene core comprising the heretoforeknown group of dimeric arylisoquinoline alkaloids, and instead contain adifferent biaryl central core of either a symmetrical or nonsymmetricalnature. For example, such novel dimeric compounds can be prepared by themethod of the present invention by use of an appropriately protected andactivated biphenyl or phenylnaphthalene building block, respectively.

Novel Dimeric Arylisoquinoline Alkaloids and Derivatives

Accordingly, the present invention also provides a new dimericarylisoquinoline alkaloid compound wherein the central core is comprisedof a biphenyl or a phenylnaphthalene. More specifically, the presentinvention provides a dimeric arylisoquinoline compound comprised offirst and second arylisoquinoline monomer halves which are the same ordifferent, wherein the first and second monomer halves have the formula(minus an H at the coupling point): ##STR1## wherein R¹, R³, and R⁴ maybe the same or different and each may be H or C₁ -C₆ alkyl, R², R⁵, R⁷,and R⁸ may be the same or different and each may be H, C₁ -C₆ alkyl, R⁹CH₂ --, or R⁹ CO--, or R⁹ SO₂, R⁹ may be H, C₁ -C₆ alkyl or aryl, andone or more of the ring positions 1, 3, 4, 2', 3', 4', 5', 6', 6, 7, and8 instead may be substituted with halo, nitro, amino, hydroxyl, thiol,acyl, C₁ -C₆ alkyl, or cyano, one or more phenolic hydroxyl group(s) mayinstead be an ester, sulfonate ester, or ether group, one or more methylether group(s) may instead be a phenolic hydroxyl group, one or morephenolic hydroxyl group(s) may instead be an aromatic hydrogensubstituent, one or more secondary amine site(s) may instead be anamide, sulfonamide, tertiary amine, alkyl quaternary ammonium salt orcorresponding Hoffmann elimination product thereof, and one or moretertiary amine site(s) may instead be a secondary amine.

The present invention also more specifically provides a dimericarylisoquinoline compound comprised of coupled first and secondarylisoquinoline monomer halves, wherein the first monomer half has theformula (minus an H at the coupling point): ##STR2## wherein R¹, R³, andR⁴ may be the same or different and each may be H or C₁ -C₆ alkyl, R²,R⁵, R⁷, and R⁸ may be the same or different and each may be H, C₁ -C₆alkyl, R⁹ CH₂ --, or R⁹ CO--, or R⁹ SO₂, R⁹ may be H, C₁ -C₆ alkyl oraryl, and one or more of the ring positions 1, 3, 4, 2', 3', 4', 5', 6',6, 7, and 8 instead may be substituted with halo, nitro, amino,hydroxyl, thiol, acyl, C₁ -C₆ alkyl, or cyano, one or more phenolichydroxyl group(s) may instead be an ester, sulfonate ester, or ethergroup, one or more methyl ether group(s) may instead be a phenolichydroxyl group, one or more phenolic hydroxyl group(s) may instead be anaromatic hydrogen substituent, one or more secondary amine site(s) mayinstead be an amide, sulfonamide, tertiary amine, alkyl quaternaryammonium salt or corresponding Hoffmann elimination product thereof, andone or more tertiary amine site(s) may instead be a secondary amine, andthe second monomer half has the formula (minus an H at the couplingpoint): ##STR3## wherein R¹, R³, and R⁴ may be the same or different andeach may be H or C₁ -C₆ alkyl, R², R⁵, R⁶, R⁷, and R⁸ may be the same ordifferent and each may be H, C₁ -C₆ alkyl, R⁹ CH₂ --, R⁹ CO--, or R⁹ SO₂--, R⁹ may be H, C₁ -C₆ alkyl or aryl, and one or more of the ringpositions 1, 3, 4, 1', 2', 3', 4', 5', 6', 7', 6, 7, and 8 may insteadbe substituted with halo, nitro, amino, hydroxyl, thiol, acyl, C₁ -C₆alkyl, or cyano, one or more phenolic hydroxyl group(s) may instead bean ester, sulfonate ester, or ether group, one or more methyl ethergroup(s) may instead be a phenolic hydroxyl group, one or more phenolichydroxyl group(s) may instead be an aromatic hydrogen substituent, oneor more secondary amine site(s) may instead be an amide, sulfonamide,tertiary amine, alkyl quaternary ammonium salt or corresponding Hoffmannelimination product thereof, and one or more tertiary amine site(s) mayinstead be a secondary amine. Further illustration of the diversity ofhomodimeric and heterodimeric arylisoquinoline alkaloids that can bemade according to the method of the present invention is given inExample 5.

EXAMPLES

The following examples further illustrate the present invention, but, ofcourse, should not be construed as in any way limiting its scope.

Example 1 Synthesis of Michellamines A and B

This example provides a more detailed description of the synthesis ofmichellamines A and B (FIG. 1) according to the method of the presentinvention. The synthetic procedure was performed as summarized in FIGS.2 and 3. Reaction conditions are given in the corresponding figurelegends. Further details of key reactions are as follows.

A 17.5 mg (39.5 μmol) sample of the isoquinolineboronic acid 8, 11.1 mg(14.2 μmol) of the binaphthalene 6, a pinch of Pd(PPh₃)₄, and 8.3 mg(43.5 μmol) Ba(OH)₂ were dissolved under argon in a mixture of 1.5 mlDME and 0.5 ml degassed water. The reaction mixture was heated for 6 hto 80° C., the solvent was removed under reduced pressure, and theresidue was purified by preparative thin-layer chromatography (petroleumether/diethyl ether, 2:1), to afford 15 mg (71%) of the quateraryl 9.

This crude product was dissolved in 2 ml dry MeOH, a pinch Pd/C (10%)was added, and the mixture was hydrogenated for 3d at ambient pressure.After removal of the solvent, the residue was dissolved in 5 mlmethanolic HCl and heated under reflux for 10 h. Removal of the solvent,yielded 7 mg (85%) from 9) of a mixture of the atropoisomericmichellamines A (1a) and B (1b), which were further purified asdescribed previously (Manfredi et al., 1991, Supra; Boyd et al., 1994,supra).

The mp, [α]p, and ¹ H NMR (CDCl₃) data for selected new compoundsfollow. 4: mp 175°-177° C., ¹ H NMR δ 7.54 (s, 1H), 7.41 (s, 1H), 7.10(s, 1H), 4.01 (s, 3H), 2.49 (s, 3H); 5: obtained as a gum, ¹ H NMR δ7.22 (s, 2H), 7.12 (br, 2H), 6.72 (s, 2H), 3.89 (s, 6H), 2.49 (s, 6H),2.43 (s, 6H, 2.12 (br, 6H); 6: mp 190°-191° C. ¹ H NMR δ 7.47 (s, 2H),7.40 (br, 2H), 6.82 (s, 2H), 3.92 (s, 6H), 2.55 (s, 6H), 2.55 (s, 6H),2.07 (s, br, 6H); 8: mp 106°-108° C., [α]_(D) =+49.3 (c=1.5 in MeOH), ¹H NMR δ 7.31-7.19 (m, 15H), 6.42 (s, 1H), 5.92 (s, br, 2H), 5.04 (s,2H), 5.02 (s, 2H), 4.08 (q, J=6.7 Hz, 1H), 3.85 (d, J=14.1 Hz, 1H),3.56-3.45 (m, 1H), 3.33 (d, J=14.1 Hz, 1H), 3.13 (dd, J=18.0, 4.6 Hz,1H), 2.79 (dd, J=18.0, 11.3 Hz, 1H), 1.35 (d, J=6.7 Hz, 3H), 1.30 (d,J=6.6 Hz, 3H).

Example 2 Preparation of Various Biaryl Building Blocks

A variety of different approaches can be used to prepare a widediversity of biaryl building blocks for use in the method of the presentinvention. For example, a suitable building block for use in the stepsdepicted in FIG. 3 for synthesis of michellamines A and B can beprepared by a suitable means different than shown in FIG. 2. Inparticular, an oxidative phenolic coupling strategy can be used toconstruct a desired biaryl from two selected aryl "halves"; the strategyis directly analogous to that used to construct the central biaryl axisbetween two naphthylisoquinoline monomers as disclosed in a previousinvention (Bringmann et al., U.S. patent application Ser. No.08/279,339). Thus, FIG. 4 illustrates the preparation of a suitablebiaryl (specifically a binaphthalene) building block by oxidativephenolic coupling of two suitably protected aryl halves, each alsocontaining the activating group desired in the biaryl building block.Typical reaction conditions are shown in the corresponding figurelegend. Further details of key reactions typically are as follows.

The naphthalene building block 10, prepared in analogy to thecorresponding bromo derivative (Bringmann et al., Heterocycles, 39,503-512 (1994) is de-isoproylated with BCl₃ to give the appropriatecoupling substrate 11. Oxidative coupling with FeCl₃ and subsequentreduction with Zn/HOAc (Laatsch et al., Liebigs Ann. Chem., 319-339,(1984)) gives the dimeric naphthalene 12, which is finally acetylatedwith AcCl to give the binaphthalene 13. Alternatively, the chlorine canbe substituted by bromine on the level of 12 by hydrogenative reductionand subsequent selective bromination with n-Bu₄ NBr₃ in the paraposition of the free hydroxy function (Berthelot et al., Can. J. Chem.,67, 2061-2066, 1989)).

Different modifications can alternatively be selected or incorporated asdesired into the aryl halves either before or after the coupling to formthe biaryl building block. Novel binaphthalenes, suitably protected andactivated, can also be prepared from other approaches, as furtherillustrated in FIG. 5. Typical reaction conditions are shown in thecorresponding figure legends 5A and 5B. Further details of key reactionstypically are as follows.

In a typical example, 14 (Bringmann et al., Heterocycles, 1994, supra)is converted to the naphthol 15 with BCl₃. After introduction of theSEM-group for the directed ortho metalation, the resulting naphthalene16 is coupled reductively (compare Lipshultz et al. Tetrahedron Lett.,31, 5567-5570,(1994)) to give 17. A directedmetalation-halogenation-sequence with t-BuLi and C₂ Br₂ Cl₄ (compareSnieckus Chem. Rev., 90, 879-933, (1990) yields the functionalizedtarget binaphthalene 18. In another typical example, the knownnaphthalene 19 is deisopropylated with BCl₃ to give the naphthol 20.After phenolic dimerization with Cu(OAc)₂ and NH₃ (Rutledge et al., U.S.Pat. No. 4,096,190) and subsequent acetylation with AcCl, the desiredbinaphthalene 21 is obtained.

By such approaches as exemplified above and as in FIGS. 2, 4, and 5,suitably protected and activated biaryl building blocks can be obtainedas necessary to make any dimeric naphthylisoquinoline compound of priorinventions (Boyd et al., U.S. Pat. No. 5,455,251; Bringmann et al, U.S.patent application Ser. No. 08/279,339). Furthermore, these sameprocedures can be used to make other suitably protected and activatedbiaryl building blocks which can be used in the method of the presentinvention to make unprecedented, new dimeric biarylisoquinolinecompounds. For example, diverse biphenyl building blocks can be preparedaccording to the schemes shown in FIG. 6. Such biphenyl building blockscan be used for the synthesis of novel new compounds of the presentinvention. "Nonsymmetrical" biaryl building blocks, such asphenylnaphthalene building blocks, can also be constructed and usedlikewise in the method of the present invention to make novel dimericarylisoquinoline compounds. Typical reaction conditions are shown in thecorresponding figure legends 6A and 6B. Further details of key reactionstypically are as follows.

In a typical example, the synthesis of 25 starts with the availablecompound 22 which is converted via 23 to 24 according to literatureprocedures (Ismail et al., J. Org. Chem., 45, 2243-2246, (1980); Sargentet al., Aust. J. Chem., 41, 1087-1097, (1988)). Cleavage of the methylether 24 with BBr3 in CH₂ Cl₂, isopropylation with isoproyl bromide inacetone and K₂ CO₃, and subsequent bromination with bromine inHOAc/NaOAc affords the biphenyl building block 25.

In another typical example, the synthesis starts with the selectivebromination of the phenol 26 with bromine and tert-BuNH₂ in toluene(analogue to Pearson et al., J. Org. Chem., 32, 2358-2360, (1967) togive 27. The boronic acid 28 is obtained after lithiation of 27 withn-BuLi and subsequent treatment with B(OMe)₃ and aqueous workup. Thecoupling with the bromo-compound 29, which may be obtained bybromination of m-cresol and subsequent benzylation, under the samecoupling conditions as in the case of Example 1 (FIG. 3), yields thenonsymmetrical biaryl 30 which is converted to the dibromo compound 31.

Example 3 Preparation of Various Isoquinoline Building Blocks

This example further illustrates some selected different variations inthe isoquinoline building blocks which may be obtained or prepared andused in the method of the present invention. For instance, diverseelectrophilic and nucleophilic isoquinoline building blocks may be madeaccording to the schemes summarized in FIGS. 7A and 7B, respectively.Typical reaction conditions are shown in the corresponding figurelegends. Further details of key reactions typically are as follows.

In typical examples for electrophilic isoquinoline building blocks, 32HBr is converted to 33 according to literature procedures (Bringmann etal., Liebigs Ann. Chem., 877-888, (1993)). 33 and tert-BuNH₂ is thendissolved in dry toluene and bromine is added. After workup andsubsequent treatment with BnBr and K₂ CO₃ in acetone, 34 is obtained.For the benzylation of 33, BnBr and K₂ CO₃ is added to a solution of 33in acetone. The bromination yields the compound 35. Reaction conditionsfor the synthesis of 36 are typical (compare Chapman et al., Synthesis,591-592, (1971)). For preparation of 36, 32 is dissolved in dry CH₂ Cl₂and TlOEt is added under argon; subsequent treatment with Tf₂ O andfollowing workup affords the desired isoquinoline derivative.

In typical examples for nucleophilic isoquinoline building blocks, 37,which can be obtained by selective bromination of 33 (for the synthesisof 33 see Bringmann et al., 1993, supra), is benzylated with BnBr.Subsequent treatment with n-BuLi yields the lithiated isoquinoline, towhich B(OMe)₃ is added. Aqueous workup affords the boronic acid 38. Forsynthesis of the isoquinoline boronic acid 39, after benzylation of 32(for the synthesis of 32 see Bringmann et al., 1993, supra) with BnBrand selective bromination, the resulting bromoisoquinoline is treatedwith n-BuLi and subsequently with B(OMe)₃ ; aqueous workup afforded thedesired boronic acid derivative.

Example 4 Construction of a Nonsymmetrical Dimeric ArylisoquinolineAlkaloid by Sequential Rather Than Simultaneous Coupling of theIsoquinoline Building Blocks to the Biaryl Building Block

Whereas Example 1 illustrates the preparation of a dimericarylisoquinoline alkaloid by simultaneous coupling of two identicalisoquinoline building blocks with a biaryl building block, this exampleillustrates the sequential coupling of a first and then a secondisoquinoline building block to a biaryl building block. This may bepreferred when the first and second isoquinoline building blocks are notidentical. A typical reaction sequence is summarized in FIG. 8. Typicalreaction conditions are shown in the corresponding figure legend.Further details of key reactions typically are as follows.

The known naphthalene 40 (Bringmann et al., Heterocycles, 1994) isdeisopropylated with BCl₃ to give the naphthol 41, which is thenoxidatively coupled with Cu(OAc)₂ and NH₃ (compare Rutledge et al., U.S.Pat. No. 4,096,190). Protection of the free hydroxy functions with BnBrand K₂ CO₃ in acetone yields the binaphthalene 42, which is converted,after mono-lithiation with n-BuLi and subsequent treatment withN-chloro-sucinimide to the bromo-chloro-binaphthalene 43. Compound 43 isselectively coupled under usual coupling conditions (see Example 1) withthe isoquinoline-boronic acid 39 to give the teraryl 44, which isconverted after lithiation and subsequent treatment with C₂ Br₂ Cl₄ tothe bromo-compound 45. The coupling with the boronic-acid 38 affords thecorresponding quateraryl, which yields after deprotection of the benzylgroups with H₂ at Pd/C (10%) the nonsymmetrical dimer 46.

Example 5 Diversity of Homodimeric and Heterodimeric ArylisoquinolineAlkaloids of the Present Invention

The present invention allows an exceedingly broad range of variations tobe incorporated individually in the first and second isoquinolinebuilding blocks and in the biaryl building bock, before and/or aftercoupling to form the homodimeric or heterodimeric arylisoquinolinealkaloid. Consequently a compound of the present invention may be drawnfrom an extraordinary diversity of variations around the dimericarylisoquinoline alkaloid theme. FIGS. 9A-G provide additional specificillustrations of such homodimers, heterodimers having differentisoquinoline parts but a symmetrical central biaryl core, andheterodimers which may have either the same or different isoquinolineparts and a nonsymmetrical central biaryl core.

All of the references cited herein, including patents, patentapplications, literature publications, and the like, are herebyincorporated in their entireties by reference.

While this invention has been described with an emphasis upon preferredembodiments, it will be obvious to those of ordinary skill in the artthat variations of the preferred compounds and methods may be used andthat it is intended that the invention may be practiced otherwise thanas specifically described herein. Accordingly, this invention includesall modifications encompassed within the spirit and scope of theinvention as defined by the following claims.

What is claimed is:
 1. A dimeric arylisoquinoline compound comprised ofcoupled first and second arylisoquinoline monomer halves which are thesame or different, wherein said first and second monomer halves have theformula (minus an H at the coupling point): ##STR4## wherein R¹, R³, andR⁴ may be the same or different and each may be H or C₁ -C₆ alkyl, R²,R⁵, R⁶, R⁷ and R⁸ may be the same or different and each may be H, C₁ -C₆alkyl R⁹ CH₂ --, R⁹ CO--, or R⁹ SO₂ --, R⁹ may be H, C₁ -C₆ alkyl oraryl and one or more of the ring positions 1, 3, 4, 2', 3', 4', 5', 6',6, 7, and 8 may instead be substituted with halo, nitro, amino,hydroxyl, thiol, acyl, C₁ -C₆ alkyl, or cyano, one or more phenolichydroxyl group(s) may instead be an ester, sulfonate ester, or ethergroup, one or more methyl ether group(s) may instead be a phenolichydroxyl group, one or more phenolic hydroxyl group(s) may instead be anaromatic hydrogen substituent, one or more secondary amine site(s) mayinstead be an amide, sulfonamide, tertiary amine, alkyl quaternaryammonium salt or corresponding Hoffmann elimination product thereof, andone or more tertiary amine site(s) may instead be a secondary amine. 2.A dimeric arylisoquinoline compound comprised of coupled first andsecond arylisoquinoline monomer halves wherein said first monomer hasthe formula (minus an H at the coupling point): ##STR5## wherein R¹, R³,and R⁴ may be the same or different and each may be H or C₁ -C₆ alkyl,R², R⁵, R⁷, and R⁸ may be the same or different and each may be H, C₁-C₆ alkyl, R⁹ CH₂ --, R⁹ CO--, or R⁹ SO₂ --, R⁹ may be H, C₁ -C₆ alkylor aryl, and one or more of the ring positions 1, 3, 4, 2', 3', 4', 5',6', 6, 7, and 8 may instead be substituted with halo, nitro, amino,hydroxyl, thiol, acyl, C₁ -C₆ alkyl, or cyano, one or more phenolichydroxyl group(s) may instead be an ester, sulfonate ester, or ethergroup, one or more methyl ether group(s) may instead be a phenolichydroxyl group, one or more phenolic hydroxyl group(s) may instead be anaromatic hydrogen substituent, one or more secondary amine site(s) mayinstead be an amide, sulfonamide, tertiary amine, alkyl quaternaryammonium salt or corresponding Hoffmann elimination product thereof, andone or more tertiary amine site(s) may instead be a secondary amine, andsaid second monomer half has the formula (minus an H at the couplingpoint): ##STR6## wherein R¹, R³, and R⁴ may be the same or different andeach may be H or C₁ -C₆ alkyl, R², R⁵, R⁶, R⁷ and R⁸ may be the same ordifferent and each may be H, C₁ -C₆ alkyl, R⁹ CH₂ --, R⁹ CO--, R⁹ SO₂--, R⁹ may be H, C₁ -C₆ alkyl or aryl, and one or more of the ringpositions 1, 3, 4, 1', 2', 3', 4', 5', 6', 7', 6, 7, and 8 may insteadbe substituted with halo, nitro, amino, hydroxyl, thiol, acyl, C₁ -C₆alkyl, or cyano, one or more phenolic hydroxyl group(s) may instead bean ester, sulfonate ester, or ether group, one or more methyl ethergroup(s) may instead be a phenolic hydroxyl group, one or more phenolichydroxyl group(s) may instead be an aromatic hydrogen substituent, oneor more secondary amine site(s) may instead be an amide, sulfonamide,tertiary amine, alkyl quaternary ammonium salt or corresponding Hoffmannelimination product thereof, and one or more tertiary amine site(s) mayinstead be a secondary amine.
 3. A dimeric arylisoquinoline compoundcomprised of coupled first and second arylisoquinoline monomer halveswhich are the same or different, wherein said first and second monomerhalves have the formula (minus an H at the coupling point): ##STR7##wherein R¹, R³, and R⁴ may be the same or different and are selectedfrom the group consisting of H and C₁ -C₆ alkyl, R², R⁵, R⁷, and R⁸ maybe the same or different and are selected from the group consisting ofH, C₁ -C₆ alkyl, R⁹ CH₂ --, and R⁹ CO--, or R⁹ SO₂, wherein R⁹ isselected from the group consisting of H, C₁ -C₆ alkyl, and aryl, and oneor more of the ring positions 1, 3, 4, 2', 3', 4', 5', 6', 6, 7, and 8instead may be substituted with a substituent selected from the groupconsisting of halo, nitro, amino, hydroxyl, thiol, acyl, C₁ -C₆ alkyl,and cyano, one or more phenolic hydroxyl group(s) may instead be anester, sulfonate ester, or ether group, one or more methyl ethergroup(s) may instead be a phenolic hydroxyl group, one or more phenolichydroxyl group(s) may instead be an aromatic hydrogen substituent, oneor more secondary amine site(s) may instead be an amide, sulfonamide,tertiary amine, alkyl quaternary ammonium salt or corresponding Hoffmannelimination product thereof, and one or more tertiary amine site(s) mayinstead be a secondary amine.
 4. A dimeric arylisoquinoline compoundcomprised of coupled first and second arylisoquinoline monomer halveswhich are the same or different, wherein said first and second monomerhalves have the formula (minus an H at the coupling point): ##STR8##wherein R¹ and R³ are H, R⁴ is selected from the group consisting of Hand C₁ -C₆ alkyl, R², R⁵, R⁶, R⁷, and R⁸ may be the same or differentand are selected from the group consisting of H, C₁ -C₆ alkyl R⁹ CH₂ --,R⁹ CO--, and R⁹ SO₂ --, wherein R⁹ is selected from the group consistingof H, C₁ -C₆ alkyl and aryl, and one or more of the ring positions 1, 3,4, 2', 3', 4', 5', 6', 6, 7, and 8 may instead be substituted with asubstituent selected from the group consisting of halo, nitro, amino,hydroxyl, thiol, acyl, C₁ -C₆ alkyl, and cyano, one or more phenolichydroxyl group(s) may instead be an ester, sulfonate ester, or ethergroup, one or more methyl ether group(s) may instead be a phenolichydroxyl group, one or more phenolic hydroxyl group(s) may instead be anaromatic hydrogen substituent, one or more secondary amine site(s) mayinstead be an amide, sulfonamide, tertiary amine, alkyl quaternaryammonium salt or corresponding Hoffmann elimination product thereof, andone or more tertiary amine site(s) may instead be a secondary amine. 5.A dimeric arylisoquinoline compound comprised of coupled first andsecond arylisoquinoline monomer halves which are the same or different,wherein said first and second monomer halves have the formula (minus anH at the coupling point): ##STR9## wherein R¹ and R³ may be the same ordifferent and selected from the group consisting of H and C₁ -C₆ alkyl,R⁴ is H, R², R⁵, R⁶, R⁷ and R⁸ may be the same or different and areselected from the group consisting of H, C₁ -C₆ alkyl, R⁹ CH₂ --, R⁹CO--, and R⁹ SO₂ --, wherein R⁹ is selected from the group consisting ofH, C₁ -C₆ alkyl and aryl, and one or more of the ring positions 1, 3, 4,2', 3', 4', 5', 6', 6, 7, and 8 may instead be substituted with asubstituent selected from the group consisting of halo, nitro, amino,hydroxyl, thiol, acyl, C₁ -C₆ alkyl, and cyano, one or more phenolichydroxyl group(s) may instead be an ester, sulfonate ester, or ethergroup, one or more methyl ether group(s) may instead be a phenolichydroxyl group, one or more phenolic hydroxyl group(s) may instead be anaromatic hydrogen substituent, one or more secondary amine site(s) mayinstead be an amide, sulfonamide, tertiary amine, alkyl quaternaryammonium salt or corresponding Hoffmann elimination product thereof, andone or more tertiary amine site(s) may instead be a secondary amine.